Listeria monocytogenes (LM) is a major pathogen in the neonate. LM is also being developed as a vaccine vehicle for heterologous vaccines from HIV to tumors. Most of these vaccines will be given to infants. Yet hardly anything is known about the immune response to LM in the neonate or infant. This is all the more surprising, as LM infection is one of the best-studied models in immunology, and excellent tools have been generated that have allowed the dissection and targeted manipulation of adult murine hostmicrobe in vivo interactions with their impact on immunity. We believe that an analysis of the neonatal immune response to LM infection employing these newly available tools will yield important mechanistic insights into not only neonatal LM infection, but also into vaccine design. We hypothesize a) that primary effector and memory T cells providing protective immunity to LM infection can be generated in the neonate; b) that it is mainly a deficit in neonatal antigen presentation that results in the neonate's heightened susceptibility to primary LM infection; and c) that it is neonate-specific regulatory pathways that provide the mechanistic underpinnings for the failure of functional memory T cell generation in the neonate in response to LM infection or vaccination. To test these hypotheses, we will take the approach successfully employed in the study of adult LM infection and vaccination, and apply these tools to the neonate. Similar to the tremendous impact the study of LM infection had on knowledge about immunology of the adult mouse, we believe our studies will address and bring to light fundamental issues in neonatal immunology and vaccinology.